PHYSIOLOGY OF HEART

CARDIAC CYCLE
Pressure Changes During the Cardiac Cycle
1. As the ventricles begin their contraction, the intraventricular pressure
rises, causing the AV valves to snap shut and produce the first heart
sound. At this time, the ventricles are neither being filled with blood
(because the AV valves are closed) nor ejecting blood (because the
intraventricular pressure has not risen sufficiently to open the
semilunar valves). This is the phase of isovolumetric contraction.
2. When the pressure in the left ventricle becomes greater than the
pressure in the aorta, the phase of ejection begins as the semilunar
valves open. The pressure in the left ventricle and aorta rises to about
120 mmHg when ejection begins and the ventricular volume
decreases.
3. As the pressure in the ventricles falls below the pressure in the
arteries, the back pressure causes the semilunar valves to snap shut
and produce the second heart sound.
The pressure in the aorta falls to 80 mmHg, while pressure in the
left ventricle falls to 0 mmHg. During isovolumetric relaxation,
the AV and semilunar valves are closed. This phase lasts until the
pressure in the ventricles falls below the pressure in the atria.
4. When the pressure in the ventricles falls below the pressure
in the atria, the AV valves open and a phase of rapid filling of
the ventricles occurs.
5. Atrial contraction (atrial systole) delivers the final amount
of blood into the ventricles immediately prior to the next
phase of isovolumetric contraction of the ventricles.

Similar events occur in the right ventricle and pulmonary

circulation, but the pressures are lower. The maximum pressure
produced at systole in the right ventricle is 25 mmHg, which falls
to a low of 8 mmHg at diastole.
 Pacemakers
• AV node and Purkinje fibers, can potentially serve as pacemakers
but are normally suppressed by action potentials originating in the
SA node. This is because their rate of spontaneous depolarization is
slower than that of the SA node.
• Thus, the potential pacemaker cells are stimulated by action
potentials from the SA node before they can stimulate themselves
through their own pacemaker potentials.
• If action potentials from the SA node are prevented from reaching
these areas (through blockage of conduction), they will generate
pacemaker potentials at their own rate and serve as sites for the
origin of action potentials; they will function as pacemakers
• A pacemaker other than the SA node is called an ectopic
pacemaker, or alternatively, an ectopic focus
 Electrical Activity of the Heart
Pacemaker Potential
• The cells of the SA node do not maintain a resting
membrane potential in the manner of resting neurons
or skeletal muscle cells.
• Instead, during the period of diastole, the SA node
exhibits a slow spontaneous depolarization called the
pacemaker potential.
• The membrane potential begins at about −60 mV and
gradually depolarizes to −40 mV, which is the threshold
for producing an action potential in these cells
• The spontaneous depolarization of the pacemaker
potential is produced by the opening of a type of channel
that, strangely, opens in response to hyperpolarization
• The hyperpolarization (approaching −60 mV) stimulus
that opens this channel occurs at the end of the
preceding action potential. This is why the cardiac
pacemaker channels are termed HCN channels (for
Hyperpolarization activated cyclic nucleotide-gated
channels).
• Once opened, this channel is permeable to both Na +
and K +.
• Because the electrochemical gradient is greater for the
entry of Na + than for the exit of K +, the entry of Na +
predominates and produces a depolarization.
• The spontaneous, automatic depolarization of
the pacemaker occurs during diastole, so it
can be termed a diastolic depolarization.
• When the diastolic depolarization reaches
threshold (about–40mV), it causes the
opening of voltage-gated Ca 2 + channels in
the plasma membrane of the pacemaker cells.
• It is the inward diffusion of Ca 2 + that
produces the upward phase of the action
potential
• The inward current of Ca 2 + also results in contraction of
these myocardial cells.
• Repolarization is produced by the opening of voltage-gated K
+ channels and the outward diffusion of K + .
• When the repolarization phase of an action potential in a
pacemaker cell is followed by a certain level of
hyperpolarization, the HCN channels in the plasma membrane
will be opened and a new pacemaker potential will begin.
• Before that, however, the action potentials produced by the
pacemaker cells will spread from myocardial cell to myocardial
cell through the gap junctions that connect them.
• Thus, action potentials will spread from the SA node through
the atria and, by means of conducting tissue, into the
ventricles.
 outflux of K+
Influx of Ca+2

Influx of Na+
 Myocardial Action Potential
• Once another myocardial cell has been
stimulated by action potentials originating in
the SA node, it produces its own action
potentials.
• The majority of myocardial cells have resting
membrane potentials of about −85 mV.
• When stimulated by action potentials from a
pacemaker region, these cells become
depolarized to threshold, at which point their
voltage-regulated Na + gates open
• The upshoot phase of the action potential of
nonpacemaker cells is due to the rapid inward
diffusion of Na + through fast Na+ channels.
• Followed by slow inward diffusion of Ca +2
through slow Ca+2 channels, which balances a
slow outward diffusion of K +. This result in
plateau phase
• Rapid repolarization at the end of the plateau
phase is achieved by the opening of voltage-
gated K + channels and the rapid outward
diffusion of K + that results.
 Plateau phase

Upshoot phase
 ECG
• Body is a good conductor of electricity
• Potential difference generated by the heart are
conducted to the body surface
• Surface electrodes placed on skin can record
this potential
• The recording obtained is called
electrocardiogram
• The recording device is called
electrocardiograph
• ECG is not a recording of action potentials, but
it does result from the production and
conduction of action potentials in the heart
 P wave
• The spread of depolarization through atria
cause a potential difference that is indicated by
an upward deflection of the ECG line.
• When about half the mass of the atria is
depolarized, this upward deflection reaches a
maximum value
because the potential
difference between
the depolarized and
unstimulated portions of
the atria is at a maximum.
• When the entire mass of the atria is
depolarized, the ECG returns to baseline
because all regions of the atria have the same
polarity. The spread of atrial depolarization
thereby creates the P wave
 QRS wave

• Conduction of the impulse into the ventricles

similarly creates a potential difference that
results in a sharp upward deflection of the
ECG line, which then returns to the baseline as
the entire mass of the ventricles becomes
depolarized.
• The spread of the depolarization into the
ventricles is thereby represented by the QRS
wave.
• The plateau phase of the cardiac action
potential is related to the S-T segment of the
ECG
• repolarization of the ventricles produces the T
wave
• depolarization of the ventricles occurs from
endocardium to epicardium, whereas
repolarization spreads in the opposite
direction, from epicardium to endocardium.
 ECG recording electrodes
• There are two types of ECG recording electrodes,
or “leads.”
• bipolar limb leads (record the voltage between
electrodes placed on the wrists and legs)
• unipolar leads (voltage is recorded between a
single rode placed on the body and an electrode
that is built into the electrocardiograph and
maintained at zero potential (ground). )
• The unipolar limb leads are placed on the right arm, left
arm, and left leg, and are abbreviated AVR, AVL, and AVF,
respectively
• The unipolar chest leads are labeled 1 through 6,
starting from the midline position.
• Thus a total of 12 standard ECG leads “view” the
changing pattern of the heart’s electrical activity from
different perspectives
• This is important because certain abnormalities are best
seen with particular leads and may not be visible at all
with other leads.
Correlation of the ECG with Heart Sounds

FIRST HEART SOUND

• Depolarization of the ventricles, as indicated by the
QRS wave, stimulates contraction by promoting the
uptake of Ca 2 + into the regions of the sarcomeres.
• The QRS wave is thus seen at the beginning of
systole.
• The rise in intraventricular pressure that results
causes the AV valves to close, so that the first heart
sound (S 1 , or lub) is produced immediately after
the QRS wave
 SECOND HEART SOUND
• Repolarization of the ventricles, as indicated
by the T wave, occurs at the same time that
the ventricles relax at the beginning of
diastole.
• The resulting fall in intraventricular pressure
causes the aortic and pulmonary semilunar
valves to close, so that the second heart
sound (S 2 , or dub) is produced shortly after
the T wave begins in an electrocardiogram.
 Atherosclerosis
• Atherosclerosis is a chronic, systemic, inflammatory and
metabolic disease and pathologic process characterized by the
accumulation of cholesterol and calcium plaque within the
arterial wall.
• form in the inner layer of the arterial wall (the intima) which is
separated from the lumen by a monolayer of endothelial cells.
• LDL cholesterol (LDL-C) can pass through the endothelial layer
and accumulate in the intima, initiating the development of
atherosclerotic plaque.
• atherosclerosis begins as a result of damage to the
endothelium.
• hypertension (high blood pressure), high blood cholesterol, and
diabetes may increase inflammation and contribute to
endothelial dysfunction
• Allowing more LDL-C to enter intima
• Once in the arterial wall, LDL-C is chemically
modified into pro-inflammatory and
immunogenic molecules, which attract
monocytes from the lumen.
• In the intima, monocytes mature into
macrophages, which in turn become overloaded
with cholesteryl ester, turning into “foam cells”.
• Attracted by signals from foam cells, smooth
muscle cells (SMCs) from the media (the middle
layer of the arterial wall) also enter the intima, as
do populations of T lymphocytes, some of which
promote atherogenesis while others mitigate it.
• The sequence of LDL-C infiltration followed by
immune cell and SMC migration into the
intima initiates the development of
atherosclerotic plaque.
• The initial plaque grows and progresses into
an atheroma — an atherosclerotic plaque
characterized by a lipid-rich core composed of
SMCs and foam cells, which continue to
migrate into the intima and can transform into
one another by a process called metaplasia.
• Because dead macrophages, foam cells, and
SMCs are not efficiently cleared from the lipid
core, it is also known as the “necrotic core”
• This necrotic core is separated from the lumen
not only by the endothelial monolayer but by
a “fibrous cap” composed of extracellular
matrix proteins secreted by the SMCs,
including collagen, elastin, proteoglycans and
glycosaminoglycans.
• Atheroma may be classified by the relative
abundance of core and cap material into “stable”
plaques, which contain a large fibrous cap and a
comparatively small necrotic core, and “vulnerable”
plaques, which contain a large necrotic core and a
thin fibrous cap.
• At least two known processes contribute to cap
thinning:
1. reduced collagen synthesis by the SMCs (mediated
by interferon gamma from T cells)
2. increased collagen breakdown (mediated by matrix
metalloproteases secreted from macrophages).
• Although stable plaques may cause chronic
ischemia by occluding the affected artery,
• vulnerable plaques are prone to rupture, an
event which may trigger thrombogenesis and
cause acute ischemic events such as stroke or
MI
 Early fatty streak.
• Beginning in childhood, this is the initial stage of the
process of atherosclerotic plaque formation
• Fatty streaks are characterized by deposition of LDL-C
particles in arterial locations prone to atherosclerosis,
such as areas of high oscillatory shear, including arterial
bifurcation points and inner walls of curvatures.
• Monocytes also begin their migration into the plaque at
this stage, turning into macrophages and, after being
loaded with chemically modified lipids, becoming foam
cells.
 Atheroma/fibro-atheroma.
• progressive stage of plaque formation,
characterized by the migration of SMCs into
the intima, attracted by signals from the foam
cells.
• LDL-C particles and macrophages progressively
accumulate into a lipid core, while SMCs
produce extracellular matrix proteins that
comprise the fibrous cap.
 Advancing atheroma
• The final stage of atheroma progression is characterized
by a large necrotic core and low SMC density, with a
correspondingly thin fibrous cap — a vulnerable plaque
prone to rupture and thrombosis.
• Atherosclerotic plaques typically progress to the advancing
atheroma stage at age 55 years to 65 years.
• Rupture occurs when the fibrous cap covering the
atheroma becomes thin and bursts, exposing the contents
of the necrotic core to the bloodstream.
• This event brings thrombogenic material from the core,
most notably tissue factor, with other clotting cascade
molecules in the bloodstream, leading to thrombin-
mediated fibrin generation, platelet aggregation and the
formation of clot.
• The dysfunctional endothelium that
characterizes atherosclerotic lesions also
contributes to thrombogenesis, as it both
lacks the anti-thrombotic properties of a
healthy endothelium and produces the pro-
thrombotic tissue factor
 Ischemic Heart Disease
• A tissue is said to be ischemic when its oxygen supply is deficient
because of inadequate blood flow
• The most common cause of myocardial ischemia is atherosclerosis of
the coronary arteries.
• An obstruction in a coronary artery, for example, may allow sufficient
coronary blood flow at rest but not when the heart is stressed by
exercise or emotional conditions.
• the increased activity of the sympathoadrenal system causes the
heart rate and blood pressure to rise, increasing the work of the heart
and raising its oxygen requirements
• mental stress can cause constriction of atherosclerotic coronary
arteries, leading to ischemia of the heart muscle
• The vasoconstriction is believed to result from abnormal function of a
damaged endothelium, which normally prevents constriction (through
secretion of paracrine regulators) in response to mental stress
 Angina pectoris
• Myocardial ischemia is associated with increased
concentrations of blood lactic acid produced by anaerobic
metabolism in the ischemic tissue.
• This condition often causes substernal pain, which may also be
referred to the left shoulder and arm, as well as to other areas.
• This referred pain is called angina pectoris.
• People with angina frequently take nitroglycerin or related
drugs that help to relieve the ischemia and pain.
• These drugs are effective because they produce vasodilation,
which improves circulation to the heart and decreases the
work that the ventricles must perform to eject blood into the
arteries.
 Myocardial infarction
• Myocardial cells are adapted for aerobic respiration
and cannot metabolize anaerobically for more than
a few minutes.
• If ischemia and anaerobic metabolism are
prolonged, necrosis (cellular death) may occur in the
areas most deprived of oxygen.
• A sudden, irreversible injury of this kind is called a
myocardial infarction, or MI.
• The lay term “heart attack,” though imprecise,
usually refers to a myocardial infarction.
• The area of dead cells is not replaced with functioning myocardial cells
because mature myocardial cells can’t divide.
• Instead, fibroblasts produce noncontractile scar tissue, which forms the
infarct.
• The area of infarcted tissue is usually relatively small if the person is
hospitalized and treated within a few hours after the onset of symptoms.
• However, after treatment that increases the supply of oxygenated blood
to the heart (so the tissue is reperfused with blood), larger numbers of
myocardial cells die because apoptosis is triggered by the production ion
of the superoxide free radical and the accumulation of intracellular
Ca2+.
• Apoptosis of surrounding myocardial tissue greatly increases the size of
the infarct and weakens the ventricle still further.
• Thus, the infarct may cause the ventricular wall to thin and distend
under pressure
• The necrosis of myocardial cells is particularly devastating because dead
myocardial cells cannot be replaced by mitosis of neighboring cells.
• Therefore, the major medical goals are to recognize myocardial ischemia
and relieve its causes before the injury becomes too great.
• Myocardial ischemia may be detected by
changes in the S-T segment of the
electrocardiogram
 Diagnosis
• Plasma concentrations of creatine phosphokinase
(CPK), for example, increase within 3 to 6 hours after
the onset of symptoms and return to normal after 3
days.
• Plasma levels of lactate dehydrogenase (LDH) reach a
peak within 48 to 72 hours after the onset of symptoms
and remain elevated for about 11 days.
• the plasma levels of cardiac muscle troponin I and
troponin T are now regarded as the most sensitive and
specific indicators of myocardial infarction, with
troponin I as particularly useful in early diagnosis.
 Arrhythmias
• abnormal heart rhythms
• A cardiac rate slower than 60 beats per
minute indicates bradycardia
• a rate faster than 100 beats per minute is
described as tachycardia
• Extremely rapid rates of electrical excitation
and contraction of either the atria or the
ventricles may produce flutter or fibrillation.
• In flutter, the contractions are very rapid (200
to 300 per minute) but are coordinated.
• In fibrillation, contractions of different groups
of myocardial cells occur at different times,
so that a coordinated pumping action of the
chambers is impossible.
 Atrial flutter & atrial fibrillation
• Atrial flutter usually degenerates quickly into atrial
fibrillation, where the disorganized production of impulses
occurs very rapidly (about 600 times per minute) and
contraction of the atria is ineffectual.
• The AV node doesn’t respond to all of those impulses,
but enough impulses still get through to stimulate the
ventricles to beat at a rapid rate (up to 150– 180 beats per
minute).
• Since the ventricles fill to about 80% of their end-diastolic
volume before even normal atrial contraction, atrial
fibrillation only reduces the cardiac output by about 15%.
• People with atrial fibrillation can thus live for many years,
although this condition is associated with increased
 ventricular fibrillation
• People with ventricular fibrillation, by
contrast, can live for only a few minutes,
unless this is extended by cardiopulmonary
resuscitation (CPR) techniques or the
fibrillation is ended by electrical defibrillation.
• Death is caused by the inability of the
fibrillating ventricles to pump blood and thus
deliver needed oxygen to the heart and brain
 Electrical defibrillation
• Fibrillation can sometimes be stopped by a strong
electric shock delivered to the chest. This procedure is
called electrical defibrillation.
• The electric shock depolarizes all of the myocardial
cells at the same time, causing them all to enter a
refractory state.
• Conduction of circus rhythms thus stops, and the SA
node can begin to stimulate contraction in a normal
fashion.
• This does not correct the initial problem that caused
circus rhythms and fibrillation, but it does keep the
person alive long enough to take other corrective
measures.
 AV Node Block
• The time interval between the beginning of atrial
depolarization—indicated by the P wave—and the
beginning of ventricular depolarization (as shown
by the Q part of the QRS complex) is called the P-R
interval
• In the normal heart, this time interval is 0.12 to 0.20
second in duration
• Damage to the AV node causes slowing of impulse
conduction and is reflected by changes in the P-R
interval. This condition is known as AV node block
 CARDIAC OUTPUT
• The cardiac output is the volume of blood pumped per
minute by each ventricle.
• The average resting cardiac rate in an adult is 70 beats
per minute;
• the average stroke volume (volume of blood pumped
per beat by each ventricle) is 70 to 80 ml per beat.
• The product of these two variables gives an average
cardiac output of 5,500 ml (5.5 L) per minute:
Cardiac output = Stroke volume × cardiac rate
(ml∕min) (ml∕beat) (beats∕min)
 Regulation of Cardiac Rate
• In the complete absence of neural influences, the heart will
continue to beat as long as the myocardial cells are alive.
• Norepinephrine from sympathetic axons and epinephrine from
the adrenal medulla also open the HCN channels of the
pacemaker cells, inducing a faster rate of diastolic depolarization.
• This causes action potentials to be produced more rapidly,
resulting in a faster cardiac rate .
• Epinephrine and norepinephrine have this effect because
(through their activation of β1 -adrenergic receptors) they
stimulate the production of cAMP in the pacemaker cells, and
the cAMP acts directly on the pacemaker HCN channels to keep
them open
• Acetylcholine, released by vagus nerve endings,
binds to muscarinic ACh receptors and causes the
opening of separate K + channels in the membrane.
• The outward diffusion of K + partially counters the
inward diffusion of Na + through the HCN channels,
producing a slower rate of diastolic depolarization.
• As a result, there is a slower rate of action potential
production and thus a slower cardiac rate
• Mechanisms that affect the cardiac rate are
said to have a chronotropic effect ( chrono =
time). Those that increase cardiac rate have a
positive chronotropic effect; those that
decrease the rate have a negative
chronotropic effect.
 Regulation of Stroke Volume
• The stroke volume is regulated by three variables:
1. the end-diastolic volume (EDV), which is the
volume of blood in the ventricles at the end of
diastole
2. the total peripheral resistance, which is the
frictional resistance, or impedance to blood flow,
in the arteries
3. the contractility, or strength, of ventricular
contraction
 1. EDV
• This is a workload imposed on the ventricles
prior to contraction, and thus is sometimes
called a preload.
• The stroke volume is directly proportional to
the preload;
• an increase in EDV results in an increase in
stroke volume. (This relationship is known as
the Frank-Starling law of the heart)
 2. contractility
• The stroke volume is also directly
proportional to contractility;
• when the ventricles contract more forcefully,
they pump more blood
 3. total peripheral resistance
• the stroke volume is inversely proportional to the
total peripheral resistance; the greater the
peripheral resistance, the lower the stroke volume
• The pressure in the arterial system before the
ventricle contracts is a function of the total
peripheral resistance—the higher the peripheral
resistance, the higher the pressure
• In order to eject blood, the pressure generated in
a ventricle when it contracts must be greater than
the pressure in the arteries (because blood flows
only from higher pressure to lower pressure).
• As blood begins to be ejected from the
ventricle, the added volume of blood in the
arteries causes a rise in mean arterial pressure
against the “bottleneck” presented by the
peripheral resistance; ejection of blood stops
shortly after the aortic pressure becomes equal
to the intraventricular pressure.
• The total peripheral resistance thus presents an
impedance to the ejection of blood from the
ventricle, or an afterload imposed on the
ventricle after contraction has begun
 Frank-Starling Law of the Heart
• demonstrate that the strength of ventricular
contraction varies directly with the end-diastolic
volume
Intrinsic Control of Contraction Strength
• EDV rises within the physiological range, the
myocardium is increasingly stretched and, as a result,
contracts more forcefully
• Prior to filling with blood during diastole, the
sarcomere lengths of myocardial cells are only about
1.5 μm. At this length, the actin filaments from each
side overlap in the middle of the sarcomeres, and the
cells can contract only weakly
• As the ventricles fill with blood, the
myocardium stretches so that the actin
filaments overlap with myosin only at the
edges of the A bands.
• This increases the number of interactions
between actin and myosin, allowing more
force to be developed during contraction.
• Also, the force of contraction is increased
because stretched myocardial cells are more
sensitive to the stimulatory effect of Ca2+,
perhaps due to the shorter distance between
thick and thin filaments
 How healthy heart compensate for
increased TPR
(1) a rise in peripheral resistance causes a decrease in
the stroke volume of the ventricle, so that
(2) more blood remains in the ventricle and the end-
diastolic volume is greater for the next cycle; as a
result,
(3) the ventricle is stretched to a greater degree in the
next cycle and contracts more strongly to eject more
blood.
This allows a healthy ventricle to sustain a normal
cardiac output
 Extrinsic Control of Contractility

Negative chronotropic effect

Positive ionotropic & chronotropic effect

Venous return

Diaphragm contracts and lowers

Regulation of Blood Volume by the Kidneys

Synthesized in hypothalamus while stored in pp

vasopressin